title: Change in the mode of inhibition of acetylcholinesterase by (4-nitrophenyl)sulfonoxyl derivatives of conformationally constrained choline analogues.
abstract: A chiral, five-step synthesis of 2-(hydroxymethyl)-2,4-dimethylmorpholine (12) from (R)- and (S)-2-methylglycidols gives an overall yield of 63%. Morpholines (R)- and (S)-12 are converted into 2-(azidomethyl)-2,4-dimethylmorpholine (15) via 2,4-dimethyl-2-[[(4-nitrophenyl)sulfonoxy]methyl]morpholine (14). The tertiary morpholines 12, 14, and 15 are quaternarized to afford 2-(hydroxymethyl)-2,4,4-trimethylmorpholinum iodide (2), 2,4,4-trimethyl-2-[[(4-nitrophenyl)sulfonoxy]methyl]morpholinium iodide (3), and 2-(azidomethyl)-2,4,4-trimethylmorpholinium iodide (4), respectively, which all inhibit acetylcholinesterase (AChE). These morpholinium inhibitors are compared with conformationally constrained aryl hemicholinium AChE inhibitors. Enantiomers of 2 and 4 are reversible competitive inhibitors of AChE, with values of Ki = 360 +/- 30 microM for (S)-2, 650 +/- 90 microM for (R)-2, 450 +/- 70 microM for (S)-4, and 560 +/- 30 microM for (R)-4, respectively. Enantiomers of 3 are noncompetitive inhibitors of AChE with values of Ki = 19.0 +/- 0.9 microM for (S)-3 and 50 +/- 2 microM for (R)-3, respectively. AChE shows a 2-fold chiral discrimination in the case of inhibition by 2 and 3. Inhibition also changes from competitive to noncompetitive when (3-hydroxyphenyl)-N,N,N-trimethylammonium iodide (18) [Ki = 0.21 +/- 0.06 microM; Lee, B. H., Stelly, T. C., Colucci, W. J., Garcia, J. G., Gandour, R. D., and Quinn, D. M. (1992) Chem. Res. Toxicol. 5, 411-418] is converted into [3-[(4-nitrophenyl)sulfonoxy]phenyl]-N,N,N-trimethylammonium iodide (5), Ki = 6.0 +/- 0.5 microM. These results indicate that the 4-nitrobenzenesulfonyl group controls the mode of inhibition.
authors.affiliation: Department of Chemistry, Virginia Tech, Blacksburg 24061-0212, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Savle
authors.forename: R A
authors.initials: RA
authors.lastname: Medhekar
authors.forename: E L
authors.initials: EL
authors.lastname: Kelley
authors.forename: J G
authors.initials: JG
authors.lastname: May
authors.forename: S F
authors.initials: SF
authors.lastname: Watkins
authors.forename: F R
authors.initials: FR
authors.lastname: Fronczek
authors.forename: D M
authors.initials: DM
authors.lastname: Quinn
authors.forename: R D
authors.initials: RD
authors.lastname: Gandour
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000818:Animals; D002794:Choline / Q000031:analogs & derivatives / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D004593:Electrophorus; D008968:Molecular Conformation; D009578:Nitrobenzenes / Q000737:chemistry*; D013450:Sulfones / Q000737:chemistry*
chemical_list: D002800:Cholinesterase Inhibitors; D009578:Nitrobenzenes; D013450:Sulfones; D000110:Acetylcholinesterase; D002794:Choline